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Design, Synthesis, and Biological Evaluation of Novel Spiro Imidazobenzodiazepines to Identify Improved Inhaled Bronchodilators

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Download Hi-Res ImageDownload to MS-PowerPointCite This:J. Med. Chem. 2023, 66, 14, 9853-9865
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    Design, Synthesis, and Biological Evaluation of Novel Spiro Imidazobenzodiazepines to Identify Improved Inhaled Bronchodilators
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    • Daniel A. Webb
      Daniel A. Webb
      Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53211, United States
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    • Michelle J. Meyer
      Michelle J. Meyer
      Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53211, United States
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    • Kayode M. Medubi
      Kayode M. Medubi
      Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53211, United States
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    • Anika S. Tylek
      Anika S. Tylek
      Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53211, United States
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    • Gene T. Yocum
      Gene T. Yocum
      Department of Anesthesiology, Columbia University, New York, New York 10032, United States
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    • M.S. Rashid Roni
      M.S. Rashid Roni
      Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53211, United States
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      Orcidhttps://orcid.org/0000-0002-3105-0540
    • Nicolas M. Zahn
      Nicolas M. Zahn
      Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53211, United States
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    • Sarah A. Swartwout
      Sarah A. Swartwout
      Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53211, United States
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    • Ahmad K. Masoud
      Ahmad K. Masoud
      Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53211, United States
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    • Charles W. Emala
      Charles W. Emala
      Department of Anesthesiology, Columbia University, New York, New York 10032, United States
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    • Douglas C. Stafford
      Douglas C. Stafford
      Pantherics Incorporated, La Jolla, California 92037, United States
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    • Leggy A. Arnold*
      Leggy A. Arnold
      Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53211, United States
      Pantherics Incorporated, La Jolla, California 92037, United States
      *Email: [email protected]. Phone: +1 4142519450. Fax: +1 4142295530.
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      Orcidhttps://orcid.org/0000-0003-1411-1572
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2023, 66, 14, 9853–9865
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    https://doi.org/10.1021/acs.jmedchem.3c00647
    Published July 7, 2023
    Copyright © 2023 American Chemical Society
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    Abstract

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    Novel gamma-aminobutyric acid receptor (GABAAR) ligands structurally related to imidazobenzodiazepine MIDD0301 were synthesized using spiro-amino acid N-carboxyanhydrides (NCAs). These compounds demonstrated increased resistance to phase 2 metabolism and avoided the formation of a 6H isomer. Compound design was guided by molecular docking using the available crystal structure of the α1β3γ2 GABAAR and correlated with in vitro binding data. The carboxylic acid containing GABAAR ligands have high aqueous solubility, low permeability, and low cell toxicity. The inability of GABAAR ligands to cross the blood–brain barrier was confirmed in vivo by the absence of sensorimotor inhibition. Pharmacological activities at lung GABAARs were demonstrated by ex vivo relaxation of guinea pig airway smooth muscle and reduction of methacholine-induced airway hyperresponsiveness (AHR) in conscious mice. We identified bronchodilator 5c with an affinity of 9 nM for GABAARs that was metabolically stable in the presence of human and mouse microsomes.

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.3c00647.

    • Synthesis procedures and copies of 1H and 13C NMR spectra for 2a–f (S8–S14), procedures and copies of 1H, 13C, and 19F NMR spectra, HPLC purity plots and HRMS spectra for 3a–g (S14–S35), procedures and copies of 1H, 13C, and 19F NMR spectra, HPLC purity plots and HRMS spectra for 4a–g (S35–S56), procedures and copies of 1H, 13C, and 19F NMR spectra, HPLC purity plots and HRMS spectra for 5a–g (S56–S77), procedures and copies of 1H, 13C, and 19F NMR spectra, HPLC purity plots and HRMS spectra for 4h, 5h, 4i, 5i, and 5j (S77–S95), concentration responses for GABAAR binding 3a–g, 4a–h, and 5a–j (S95–S101), concentration responses for cellular toxicity studies 3a–g, 4a–i, and 5a–j (S101–S103), temperature dependent NMR studies with 3d and 4a (S103 and S104), synthesis procedures and copies of 1H and 13C NMR spectra for 2s (S104 and S105) (PDF)

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    This article is cited by 4 publications.

    1. Yiqing Fan, Zeqi Zeng, Jiaxian Mo, Zike Wang, Hongyu Jiang, Juanjuan Liu, Hai Qian, Wei Shi. Design, Synthesis, and Biological Assessment of Novel Aminobenzidazole Agonists Targeting the Stimulator of Interferon Genes (STING) Receptor Signaling Pathway for Oncology Immunotherapy. ChemMedChem 2025, 20 (7) https://doi.org/10.1002/cmdc.202400695
    2. Zhangxu He, Weiguang Yang, Feifei Yang, Jingyu Zhang, Liying Ma. Innovative medicinal chemistry strategies for enhancing drug solubility. European Journal of Medicinal Chemistry 2024, 279 , 116842. https://doi.org/10.1016/j.ejmech.2024.116842
    3. Ashokkumar Krishnan, Sriraghavan Kamaraj. High-yielding regioselective synthesis of p -quinone fused 5-substituted-1,4-benzodiazepine scaffolds via Pictet–Spengler type cycloannulation. New Journal of Chemistry 2024, 48 (22) , 10045-10052. https://doi.org/10.1039/D4NJ00993B
    4. Long Zhao, Mao-Lin Yang, Hao-Ran Chen, Ming-Wu Ding. New efficient synthesis of polysubstituted benzo[d]pyrido[1′,2':1,2]imidazo[4,5-f][1,3]diazepines and pyrido[2′,1':2,3]imidazo[1,5-c]quinazolin-7-ium salts via Groebke-Blackburn-Bienaymé/Staudinger/aza-Wittig/carbodiimide-mediated annulation sequence. Tetrahedron 2024, 152 , 133834. https://doi.org/10.1016/j.tet.2024.133834
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2023, 66, 14, 9853–9865
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.3c00647
    Published July 7, 2023
    Copyright © 2023 American Chemical Society
    Request reuse permissions

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